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@article{Walker:2017:cid/cix231,
author = {Walker, NF and Wilkinson, KA and Meintjes, G and Tezera, LB and Goliath, R and Peyper, JM and Tadokera, R and Opondo, C and Coussens, AK and Wilkinson, RJ and Friedland, JS and Elkington, PT},
doi = {cid/cix231},
journal = {Clinical Infectious Diseases},
pages = {121--132},
title = {Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study},
url = {http://dx.doi.org/10.1093/cid/cix231},
volume = {65},
year = {2017}
}

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TY  - JOUR
AB  - Background. Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, butthe underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a keyprocess but has not been systematically studied in HIV-associated TB.Methods. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)–infected and –uninfected TB patientsand controls, and a prospective cohort study of HIV-1–infected TB patients at risk of TB immune reconstitution inflammatorysyndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasmaprocollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM)by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacteriumtuberculosis and extracellular matrix in a 3D model of TB granuloma formation.Results. MMP activity differed between HIV-1–infected and –uninfected TB patients and corresponded with specific TB clinicalphenotypes. HIV-1–infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation,but increased plasma PIIINP, compared to HIV-1–uninfected TB patients. Elevated extrapulmonary extracellular matrix turnoverwas associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likelyneutrophil derived and M. tuberculosis–antigen driven. Mycobacterium tuberculosis–induced matrix degradation was suppressed bythe MMP inhibitor doxycycline in vitro.Conclusions. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrixturnover in HIV-1–infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibitionis a potential host-directed therapy
AU  - Walker,NF
AU  - Wilkinson,KA
AU  - Meintjes,G
AU  - Tezera,LB
AU  - Goliath,R
AU  - Peyper,JM
AU  - Tadokera,R
AU  - Opondo,C
AU  - Coussens,AK
AU  - Wilkinson,RJ
AU  - Friedland,JS
AU  - Elkington,PT
DO  - cid/cix231
EP  - 132
PY  - 2017///
SN  - 1058-4838
SP  - 121
TI  - Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study
T2  - Clinical Infectious Diseases
UR  - http://dx.doi.org/10.1093/cid/cix231
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000403459300022&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/49996
VL  - 65
ER  -

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